Rare copy-number variants as modulators of common disease susceptibility

**Background:** Copy-number variants (CNVs) are deletions or duplications of DNA fragments ≥50 bp that can alter gene dosage and contribute to disease. While CNVs are known to cause rare genomic disorders (GDs), their impact on common diseases in the general population is poorly understood. This study aimed to systematically investigate the role of rare CNVs in modulating susceptibility to 60 common diseases using large-scale biobank data.

**Methods:** The discovery cohort comprised 331,522 unrelated white British UK Biobank (UKBB) participants. CNVs were called from microarray data using PennCNV and filtered for high confidence (|QS|>0.5). Four association models were tested: mirror (additive effect of each copy), U-shape (any deviation from copy-neutral), duplication-only, and deletion-only. Genome-wide significance was set at p ≤ 7.5×10⁻⁶. Stepwise conditional analysis identified independent signals, which were mapped to 45 unique CNV regions (CNVRs). Validation included Fisher tests, residual regression, time-to-event Cox proportional hazards models, and replication in 90,211 unrelated Estonian Biobank (EstBB) individuals. BMI confounding was assessed for 25 associations where both disease risk and CNV status associated with BMI.

**Key Results:** The study identified 73 signals (70 disease associations and 3 disease burden associations) involving 40 diseases, all indicating that CNVs increased disease risk and caused earlier onset. Signals mapped to 45 unique CNVRs, nine of which linked to known GDs. 16% of associations (12/73) were likely driven by the CNV's effect on BMI. Notable findings included: 17q12 deletions and duplications both increased chronic kidney disease risk (OR_U-shape = 6.5, 95% CI [3.4; 12.1], p = 5.9×10⁻⁹), with 33.3% of deletion carriers and 16.9% of duplication carriers affected versus 4.4% in copy-neutral individuals. 16p13.11 deletions increased risk for epilepsy (OR_del = 6.2, 95% CI [2.8; 13.4], p = 4.4×10⁻⁶) and kidney stones (OR_del = 5.9, 95% CI [2.9; 11.9], p = 7.3×10⁻⁷), with fine-mapping implicating ABCC6 for kidney stones. 15q13 duplications increased risk for acute kidney injury (OR_dup = 4.6, 95% CI [2.5; 8.4], p = 7.1×10⁻⁷), replicated in EstBB (p = 2.7×10⁻⁴). The total CNV burden accounted for only ~0.02% of the UKBB disease burden, but burden associations were mainly driven by known GD CNVRs, with 49 of 60 diseases (82%) associated with CNVs through either GWAS or burden analysis.

**Clinical Implications:** This study demonstrates that rare CNVs, particularly those at known GD regions, are important modulators of common disease susceptibility in the general population, with all detected associations increasing risk and causing earlier onset. The findings provide actionable insights for anticipating later-onset comorbidities in carriers of recurrent CNVs, such as kidney stones in 16p13.11 deletion carriers or chronic kidney disease in 17q12 CNV carriers. The results advocate for a model of variable CNV expressivity and penetrance, where CNVs can cause a spectrum from rare Mendelian disorders to common diseases, and highlight the potential for improved clinical characterization and preventive strategies for CNV carriers.